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TNF-α-mediated inflammation in cerebral aneurysms: A potential link to growth and rupture

Authors Jayaraman T, Paget A, Shin YS, Li X, Mayer J, Chaudhry HW, Niimi Y, Silane M, Berenstein A

Published 8 August 2008 Volume 2008:4(4) Pages 805—817


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Thottala Jayaraman1,2, Andrew Paget1, Yang Sam Shin1, Xiaguai Li1, Jillian Mayer1, Hina W Chaudhry2, Yasunari Niimi3, Michael Silane4, Alejandro Berenstein3,

1Department of Neurosurgery, St. Luke’s Roosevelt Hospital Center, New York, NY, USA; 2Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 3Endovascular Surgery, St. Luke’s Roosevelt Hospital Center, New York; and 4Division of Vascular Surgery, Beth Israel Medical Center, New York, NY, USA

Abstract: Intracranial aneurysm (IA) rupture is one of the leading causes of stroke in the United States and remains a major health concern today. Most aneurysms are asymptomatic with a minor percentage of rupture annually. Regardless, IA rupture has a devastatingly high mortality rate and does not have specific drugs that stabilize or prevent aneurysm rupture, though other preventive therapeutic options such as clipping and coiling of incidental aneurysms are available to clinicians. The lack of specific drugs to limit aneurysm growth and rupture is, in part, attributed to the limited knowledge on the biology of IA growth and rupture. Though inflammatory macrophages and lymphocytes infiltrate the aneurysm wall, a link between their presence and aneurysm growth with subsequent rupture is not completely understood. Given our published results that demonstrate that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α), is highly expressed in human ruptured aneurysms, we hypothesize that pro-inflammatory cell types are the prime source of TNF-α that initiate damage to endothelium, smooth muscle cells (SMC) and internal elastic lamina (IEL). To gain insights into TNF-α expression in the aneurysm wall, we have examined the potential regulators of TNF-α and report that higher TNF-α expression correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium (Ca2+)i and Toll like receptors (TLR) that mediate innate immunity. Moreover, the reduction of tissue inhibitor of metalloproteinase-1 (TIMP-1) expression provides insights on why higher matrix metalloproteinase (MMP) activity is noted in ruptured IA. Because TNF-α is known to amplify several signaling pathways leading to inflammation, apoptosis and tissue degradation, we will review the potential role of TNF-α in IA formation, growth and rupture. Neutralizing TNF-α action in the aneurysm wall may have a beneficial effect in preventing aneurysm growth by reducing inflammation and arterial remodeling.

Keywords: innate immunity, TNF-α, inflammation, intracranial aneurysm growth

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